Specific reading disability (dyslexia) affects 5 to 10% of school children, with its effects persisting into adulthood. There is substantial evidence of genetic influence on reading disability, and segregation analysis has been consistent with a major gene influence (Pennington et al., 1991). Analytical and molecular methods now exist for detection of genes of genes influencing complex traits such as reading disability, and we have used these methods to tentatively localize one quantitative trait locus to the short arm of chromosome 6 (Cardon et al., 1994, 1995). However, this locus does not account for the full genetic variation, and other genes undoubtedly exist. We have already ascertained a unique population of 19 kindreds, selected for an autosomal dominant pattern of inheritance, that is particularly suitable for gene localization, since the population would be enriched for major genes. We will use both parametric and non-parametric linkage analysis and qualitative and quantitative reading disability phenotypes to localized these additional genes. These phenotypes will include specific measures of abilities that are critical to reading, such as phonological segmentation, phonological coding, and orthographic coding, to determine if these phenotypes characterize a particular locus. A stepwise search strategy will be used, starting with an automated genome screen with markers spaced approximately 10 cM apart and spanning the entire genome. Additional markers will be typed in regions showing indications of linkages, and this region will also be typed in an independent sample of 175 nuclear families in which at least one child has reading disability, to confirm the linkage and determine the optimal phenotype. If further analysis confirms linkage in a region, candidate genes will be identified and mutational analysis will be used to identify functional mutations. Linkage and association analysis will be used to verify that a candidate gene effects reading disability in the 175 nuclear families.